Function: Hardingham et al. (2002) reported that synaptic and extrasynaptic NMDA receptors have opposite effects on CREB (OMIM:123810) function, gene regulation, and neuronal survival. Calcium entry through synaptic NMDA receptors induced CREB activity and brain-derived neurotrophic factor (BDNF; OMIM:113505) gene expression as strongly as did stimulation of L-type calcium channels. In contrast, calcium entry through extrasynaptic NMDA receptors, triggered by bath glutamate exposure or hypoxic/ischemic conditions, activated a general and dominant CREB shut-off pathway that blocked induction of BDNF expression. Synaptic NMDA receptors have antiapoptotic activity, whereas stimulation of extrasynaptic NMDA receptors caused loss of mitochondrial membrane potential (an early marker for glutamate-induced neuronal damage) and cell death.

Function: Lee et al. (2002) reported that dopamine D1 receptors (OMIM:126449) modulate NMDA glutamate receptor-mediated functions through direct protein-protein interactions. Two regions in the D1 receptor carboxyl tail could directly and selectively couple to NMDA glutamate receptor subunits NR1-1A and NR2A. While one interaction was involved in the inhibition of NMDA receptor-gated currents, the other was implicated in the attenuation of NMDA receptor-mediated excitotoxicity through a phosphatidylinositol 3-kinase (see OMIM:171833)-dependent pathway.

Function: Wang et al. (2003) showed that transient forebrain ischemia in rat caused hippocampal CA1 pyramidal neuron cell death. Ischemia in these cells led to an increase in p25, the truncated and deleterious form of the neuron-specific activator p35 (OMIM:603460), which was associated with prolonged activation of cyclin-dependent kinase-5 (CDK5; OMIM:123831). Activated CDK5 phosphorylated the NMDA receptor-2A subunit at ser1232, resulting in enhanced current activity through NMDA synaptic receptors. Inhibition of CDK5 or of the interaction between CDK5 and NR2A protected CA1 pyramidal cells from ischemic insult. Wang et al. (2003) concluded that modulation of NMDA receptors by CDK5 is the primary intracellular event underlying ischemic injury of CA1 pyramidal neurons.

Function: Using hippocampal slice preparations, Liu et al. (2004) showed that selectively blocking NMDA receptors that contain the NR2B subunit (OMIM:138252) abolished the induction of long-term depression but not long-term potentiation. In contrast, preferential inhibition of NR2A-containing NMDA receptors prevented the induction of long-term potentiation without affecting long-term depression production. Liu et al. (2004) concluded that their results demonstrated that distinct NMDA receptor subunits are critical factors that determine the polarity of synaptic plasticity.

Function: Rusakov et al. (2004) commented on the paper by Liu et al. (2004), suggesting that because NR2B, but not NR2A, receptors occur outside synapses and can be activated by glutamate spillover, this principle may underlie synaptic homeostasis. Wong et al. (2004) responded to the comments by Rusakov et al. (2004) by stating that although they agreed that activation of extrasynaptic NR2B receptors by glutamate spillover may lead to heterosynaptic long-term depression, the data also supported a role of synaptic NR2B receptors in homosynaptic long-term depression. The proposed role of extrasynaptic NMDA receptor-mediated long-term depression in synaptic homeostasis may thus be temporally limited.

Function: By examining the kinetics of transmitter binding and channel gating in single-channel currents from recombinant NR1/NR2A receptors, Popescu et al. (2004) showed that the synaptic response to trains of impulses is determined by the molecular reaction mechanism of the receptor. The rate constants estimated for the activation reaction predicted that, after binding neurotransmitter, receptors hesitate for approximately 4 milliseconds in a closed high-affinity conformation before they either proceed towards opening or release neurotransmitter, with about equal probabilities. Because only about half of the initial fully occupied receptors become active, repetitive stimulation elicits currents with distinct waveforms depending on the pulse frequency.

Function: Among 304 Swiss individuals tested and genotyped, de Quervain and Papassotiropoulos (2006) found a significant association (p = 0.00008) between short-term episodic memory performance and genetic variations in a 7-gene cluster consisting of the ADCY8 (OMIM:103070), PRKACG (OMIM:176893), CAMK2G (OMIM:602123), GRIN2A, GRIN2B, GRM3 (OMIM:601115), and PRKCA (OMIM:176960) genes, all of which have well-established molecular and biologic functions in animal memory. Functional MRI studies in an independent set of 32 individuals with similar memory performance showed a correlation between activation in memory-related brain regions, including the hippocampus and parahippocampal gyrus, and genetic variability in the 7-gene cluster. De Quervain and Papassotiropoulos (2006) concluded that these 7 genes encode proteins of the memory formation signaling cascade that are important for human memory function.

Function: Micu et al. (2006) showed that NMDA glutamate receptors mediate calcium ion accumulation in central myelin in response to chemical ischemia in vitro. Using 2-photon microscopy, they imaged fluorescence of the calcium ion indicator X-rhod-1 loaded into oligodendrocytes and the cytoplasmic compartment of the myelin sheath in adult rat optic nerves. The AMPA/kainate receptor antagonist NBQX completely blocked the ischemic calcium ion increase in oligodendroglial cell bodies, but only modestly reduced the calcium ion increase in myelin. In contrast, the calcium ion increase in myelin was abolished by broad-spectrum NMDA receptor antagonists, but not by more selective blockers of NR2A and NR2B subunit-containing receptors. In vitro ischemia causes ultrastructural damage to both axon cylinders and myelin. NMDA receptor antagonism greatly reduced the damage to myelin. NR1, NR2, and NR3 subunits were detected in myelin by immunohistochemistry and immunoprecipitation, indicating that all necessary subunits were present for the formation of functional NMDA receptors. Micu et al. (2006) concluded that their data showed that the mature myelin sheath can respond independently to injurious stimuli. Given that axons are known to release glutamate, the finding that the calcium ion increase is mediated in large part by activation of myelinic NMDA receptors suggested a new mechanism of axomyelinic signaling.

Summary

Top-ranked sequences

Query  1300 RELDLSRPSRSISLKDRERLLEGNFYGSLF#SVPXXXXXXXXXXXFPQGLEDSKRSKSLLP 1359
            ||||||||||||||||||||||||||||||#|||           ||||||||||||||||
Sbjct  1300 RELDLSRPSRSISLKDRERLLEGNFYGSLF#SVPSSKLSGKKSSLFPQGLEDSKRSKSLLP 1359

Query  1300 RELDLSRPSRSISLKDRERLLEGNFYGSLF#SVPXXXXXXXXXXXFPQGLEDSKRSKSLLP 1359
            ||||||||||||||||||||||||||||||#|||           ||||||||||||||||
Sbjct  1300 RELDLSRPSRSISLKDRERLLEGNFYGSLF#SVPSSKLSGKKSSLFPQGLEDSKRSKSLLP 1359

Query  1300 RELDLSRPSRSISLKDRERLLEGNFYGSLF#SVPXXXXXXXXXXXFPQGLEDSKRSKSLLP 1359
            ||||||||||||||||||||||||||||||#|||           ||||||||||||||||
Sbjct  1300 RELDLSRPSRSISLKDRERLLEGNFYGSLF#SVPSSKLSGKKSSLFPQGLEDSKRSKSLLP 1359

Query  1300 RELDLSRPSRSISLKDRERLLEGNFYGSLF#SVPXXXXXXXXXXXFPQGLEDSKRSKSLLP 1359
            ||+|||||||||||||||||||||||||||#|||           ||||||||||||||||
Sbjct  1224 REIDLSRPSRSISLKDRERLLEGNFYGSLF#SVPSSKLSGKKSSLFPQGLEDSKRSKSLLP 1283

Query  1300 RELDLSRPSRSISLKDRERLLEGNFYGSLF#SVPXXXXXXXXXXXFPQGLEDSKRSKSLLP 1359
            ||+||||||||||||||||||||| |||||#|||           ||||||||||||||||
Sbjct  1300 REIDLSRPSRSISLKDRERLLEGNLYGSLF#SVPSSKLLGNKSSLFPQGLEDSKRSKSLLP 1359

Query  1300 RELDLSRPSRSISLKDRERLLEGNFYGSLF#SVPXXXXXXXXXXXFPQGLEDSKRSKSLLP 1359
            ||+||||||||||||||||||||| |||||#|||           ||||||||||||||||
Sbjct  1300 REIDLSRPSRSISLKDRERLLEGNLYGSLF#SVPSSKLLGNKSSLFPQGLEDSKRSKSLLP 1359

Query  1300 RELDLSRPSRSISLKDRERLLEGNFYGSLF#SVPXXXXXXXXXXXFPQGLEDSKRSKSLLP 1359
            ||+||||||||||||||||||||| |||||#|||           ||||||||||||||||
Sbjct  1300 REIDLSRPSRSISLKDRERLLEGNLYGSLF#SVPSSKLLGNKSSLFPQGLEDSKRSKSLLP 1359

Query  1300 RELDLSRPSRSISLKDRERLLEGNFYGSLF#SVPXXXXXXXXXXXFPQGLEDSKRSKSLLP 1359
            ||+||||||||||||||||||||| |||||#|||           ||||||| ||||||||
Sbjct  1300 REMDLSRPSRSISLKDRERLLEGNLYGSLF#SVPSSKLSGNKSSLFPQGLEDRKRSKSLLP 1359

Query  1300 RELDLSRPSRSISLKDRERLLEGNFYGSLF#SVPXXXXXXXXXXXFPQGLEDSKRSKSLLP 1359
            ||+| ||||||||||||||||||| |||||#|||           ||||||  ||||||||
Sbjct  1072 REVDPSRPSRSISLKDRERLLEGNLYGSLF#SVPSSKLAGNKGSLFPQGLEVGKRSKSLLP 1131

Query  1300 RELDLSRPSRSISLKDRERLLEGNFYGSLF#SVPXXXXXXXXXXXFPQGLEDSKRSKSLLP 1359
            ||+|| ||||||||||+||||||| |||||#|||           | | |||+|||||| |
Sbjct  1305 REIDLGRPSRSISLKDKERLLEGNLYGSLF#SVPSSKLLGNKGSLFSQALEDTKRSKSLFP 1364

Query  1300 RELDLSRPSRSISLKDRERLLEGNFYGSLF#SVPXXXXXXXXXXXFPQGLEDSKRSKSLLP 1359
            ||+|| ||||||||||+|+ |+ + | |+|#|||               |||||||||| |
Sbjct  1294 REIDLGRPSRSISLKDKEKFLQSSPYASMF#SVPSSKLLSNKASLLTHALEDSKRSKSLYP 1353

Query  1300 RELDLSRPSRSISLKDRERLLEGNFYGSLF#SVPXXXXXXXXXXXFPQGLEDSKRSKSLLP 1359
            +|+||+||+||+|||+++| || + | ++|#++            | + ||+||||||| |
Sbjct  1289 KEIDLNRPARSVSLKEKDRFLEDSPYANMF#NIKADKLFGSRSMLFNRNLEESKRSKSLYP 1348

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